Parkinson's disease (PD) is the second most common neurodegenerative disease, affecting approximately 1% of the population older than 65. Recent research has identified a metal ion transporter, ATP13A2, that that when mutated leads to early-onset PD. The Lindquist lab has found that the Saccharomyces cerevisiae homolog of this protein, YOR291 wp, suppresses the toxicity of another PD protein, ?-synuclein. The goal of this proposal is to understand the biological function of ATP13A2/YOR291wp and the role metal ion transport plays in ?-synuclein toxicity via the following specific aims: 1) Characterize YOR291w function using molecular genetic and biochemical approaches 2) Investigate the effects of metal ion transporters on alpha-synuclein toxicity using high-throughput screening and microarrays and 3) confirm all results in neuronal PC12 cell line. The results from these experiments will identify the biological function of ATP13A2/YOR291wp, as well as the role metal ions play in ?-synuclein toxicity and the development of PD. Public Health statement: Parkinson's disease is a common neurodegenerative disease. I will investigate the function of a protein shown to cause familial Parkinson's disease, as well as the role metal ions play in the development of Parkinson's disease. Understanding how Parkinson's disease progresses will lead to the identification of new therapeutic targets.